The involvement of serotonergic system in the antidepressant effect of zinc in the forced swim test

Recent preclinical data indicated the antidepressant-like activity of zinc in different tests and models of depression. The present study investigates the involvement of the serotonergic system in zinc activity in the forced swim test (FST) in mice and rats. The combined treatment of sub-effective doses of zinc (hydroaspartate, 2.5 mg Zn/kg) and citalopram (15 mg/kg), fluoxetine (5 mg/kg) but not with reboxetine (2.5 mg/kg) significantly reduces the immobility time in the FST in mice. These treatments had no influence on the spontaneous locomotor activity. Moreover, while the antidepressant-like effect of zinc (5 mg/kg) in the FST was significantly blocked by pretreatment with inhibitor of serotonin synthesis, p-chlorophenylalanine (pCPA, 3 × 200 mg/kg), 5HT-2_A/C receptor antagonist, ritanserin (4 mg/kg) or 5HT-1A receptor antagonist, WAY 1006335 (0.1 mg/kg), the zinc-induced reduction in the locomotor activity was not affected by these serotonin modulator agents. These results indicate the specific involvement of the serotonergic system in antidepressant but not the motion behavior of zinc in mice. Also, an increase in the swimming but not climbing parameter of the rat FST observed following zinc administration (2.5 and 5 mg Zn/kg) indicates the serotonin pathway participation. This present data indicates that the antidepressant-like activity of zinc observed in the FST involves interaction with the serotonergic system.     

Pioglitazone inhibits platelet function and potentiates the effects of aspirin: a prospective observation study

Background

Thiazolidinediones (TZDs) are agonists of PPARγ and exert beneficial metabolic effects in patients with diabetes. They may also affect platelet function.

Objectives

To characterize potential platelet inhibitory effect of pioglitazone alone and in the presence of aspirin.

Methods

20 normal and 20 diabetic subjects were enrolled in a prospective study. On day 1, a blood sample was obtained at baseline and a second one after ingestion of 30 mg of pioglitazone. PRP was prepared and platelet aggregation and release were evaluated using ADP, collagen and arachidonic acid as agonists. Subjects returned at 6-9 days later after ingesting a single 81 mg dose of aspirin and a third blood sample was obtained. The subjects then again ingested 30 mg of pioglitazone and a fourth and final blood sample was obtained. Platelet aggregation and release were measured. PRP was incubated with thrombin to activate platelets, and the serum was separated and assayed for thromboxane B2, TGFβ and CD40L

Results

Pioglitazone alone did not affect aggregation with arachidonic acid. However, following ingestion of both aspirin and pioglitazone aggregation was significantly decreased compared to aspirin alone (P < 0.0001). Pioglitazone also potentiated aspirin-induced inhibition of ATP release using either arachidonic acid or collagen. Following pioglitazone alone, TXB₂ release was 32,719 ± 3,585 pg/ml which was significantly reduced compared to baseline (42,075 ± 4,479, P = 0.0004). Pioglitazone also potentiated the inhibition of TXB₂ release by aspirin.

Conclusion

Pioglitazone inhibits platelet function and potentiates the inhibitory effects of aspirin.     

Evidence for the involvement of the serotonergic 5-HT2A/C and 5-HT3 receptors in the antidepressant-like effect caused by oral administration of bis selenide in mice

The present study investigated a possible antidepressant-like activity of bis selenide using two predictive tests for antidepressant effect on rodents: the forced swimming test (FST) and the tail suspension test (TST). Bis selenide (0.5–5 mg/kg, p.o.) decreased the immobility time in the mouse FST and TST. The anti-immobility effect of bis selenide (1 mg/kg, p.o.) in the TST was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis), ketanserin (1 mg/kg, i.p., a 5-HT_2A/2C receptor antagonist), and ondasentron (1 mg/kg, i.p., a 5-HT₃ receptor antagonist). Pretreatment of mice with prazosin (1 mg/kg, i.p., an α₁-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a β-adrenoceptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist), or WAY 100635 (0.1 mg/kg, s.c., a selective 5-HT_1A receptor antagonist) did not block the antidepressant-like effect of bis selenide (1 mg/kg, p.o.) in the TST. Administration of bis selenide (0.1 mg/kg, p.o.) and fluoxetine (1 mg/kg), at subeffective doses, produced an antidepressant-like effect in the TST. Bis selenide did not alter Na⁺ K⁺ ATPase, MAO-A and MAO-B activities in whole brains of mice. Bis selenide produced an antidepressant-like effect in the mouse TST and FST, which may be related to the serotonergic system (5-HT_2A/2C and 5-HT₃ receptors).     

Intra-lateral septal infusions of folic acid alone or combined with various antidepressant drugs produce antidepressant-like actions in male Wistar rats forced to swim

Intra-cerebral administrations of folic acid produce antidepressant-like effects; either alone or combined with several antidepressant drugs. However, the specific limbic structures implied in the antidepressant-like actions of folic acid are un-known. Thus, intra-lateral septal infusions of folic acid (5.0 nmol, P < 0.05; 10.0 nmol, P < 0.05) or oral administrations of folic acid (50 mg/kg, P < 0.05, p.o.; 75.0; mg/kg, P < 0.05, p.o.) or systemic administrations of fluoxetine (20.0 mg/kg, P < 0.05; 25.0 mg/kg, P < 0.05) reduced immobility by increasing swimming behavior in the forced swimming test (FST) of male Wistar rats. Conversely, desipramine (10.0 mg/kg, P < 0.05; 15.0 mg/kg, P < 0.05) reduced immobility by increasing climbing behavior. Subthreshold doses of folic acid (2.5 nmol/intra-LSN) combined with subthreshold doses of folic acid (25.0 mg/kg, p.o., P < 0.05) or with subthreshold doses of fluoxetine (15.0 mg/kg, P < 0.05) and they produced antidepressant-like effects which were canceled by ketanserin. In conclusion, intra-lateral septal infusions of folic acid alone or combined with systemic doses of folic acid or fluoxetine reduced immobility in the FST. These antidepressant-like actions, probably, were due to modifications of the serotonergic system since swimming behavior was increased and these effects were canceled by ketanserin.     

Putrescine produces antidepressant-like effects in the forced swimming test and in the tail suspension test in mice

Putrescine, a polyamine present at high concentrations in the mammalian brain, was suggested to play a role in the modulation of depression. Thus, this study investigated the effect of putrescine in the mouse forced swimming test (FST) and in the tail suspension test (TST), two models predictive of antidepressant activity. Putrescine significantly reduced the immobility time both in the FST and in the TST (dose range of 1–10 mg/kg, i.p.), without changing locomotion in an open-field. I.c.v. injection of putrescine (0.1–10 nmol/site) also reduced the immobility time in the FST and in the TST. The pretreatment of mice with arcaine (1 mg/kg, i.p., an antagonist of the polyamine-site of NMDA receptor) completely blocked the anti-immobility effect of putrescine (10 mg/kg, i.p.). A subeffective dose of putrescine (0.1 mg/kg, i.p.) produced a synergistic antidepressant-like effect with agmatine (0.001 mg/kg, i.p.) in the FST. Moreover, a subeffective dose of putrescine (0.01 nmol/site, i.c.v.) produced a synergistic antidepressant-like effect with arcaine (50 μg/site, i.c.v.). The results indicate that putrescine produces antidepressant-like effects in the FST that seems to be mediated through its interaction with the polyamine-site of NMDA receptors.     

The folic acid combined with 17-β estradiol produces antidepressant-like actions in ovariectomized rats forced to swim

Folic acid or 17-β estradiol produces antidepressant effects, either alone or combined with several antidepressants. However, the antidepressant-like actions of folic acid combined with 17-β estradiol in the forced swimming test (FST) have not been tested before. Thus, in the present study, ovariectomized female rats received folic acid (5.0 nmol/i.c.v., P < 0.05; 10.0 nmol/ i.c.v., P < 0.05; or 50 mg/kg, P < 0.05, p.o.; 75.0; mg/kg, P < 0.05, p.o.), or fluoxetine (20.0 mg/kg, P < 0.05; 25.0 mg/kg, P < 0.05) or 17-β estradiol (10.0 μg/rat, P < 0.05; 20.0 μg/rat, P < 0.05) and they displayed reduced immobility by increasing swimming behavior when they were tested in the FST. Combination of subthreshold doses of folic acid (2.5 nmol/i.c.v.; or 25.0 mg/kg, p.o.) with subthreshold doses of 17-β estradiol (5.0 μg/rat, P < 0.05) or with subthreshold doses of fluoxetine (15.0 mg/kg, P < 0.05) produced antidepressant-like actions. Ketanserin was used to evaluate the participation of the drugs used in the serotonergic pathway; ketanserin cancelled the antidepressant-like actions of the several combinations used. In conclusion, folic acid alone or combined with estradiol or fluoxetine in the FST reduced immobility in the FST. These antidepressant-like actions probably were due to modifications of the serotonergic system since swimming behavior was increased and these effects were cancelled by ketanserin.     

Facilitating antidepressant-like actions of estrogens are mediated by 5-HT1A and estrogen receptors in the rat forced swimming test

Previous studies have shown that 17beta-estradiol (E2) induces antidepressant-like actions per se and potentiates those produced by fluoxetine (FLX) in the forced swimming test (FST). The aim of the present work was to explore the participation of serotonin 1A receptors (5-HT1A) and estrogen receptors (ERs) in the antidepressant-like actions of E2, FLX or their combination in the FST. Although all antidepressants reduce behavioral immobility, antidepressants that modulate serotonergic neurotransmission increase swimming behavior whereas those that modulate the catecholaminergic neurotransmission increase climbing behavior. Thus, using this animal model, it is possible to infer which neurotransmitter system is modulating the action of an antidepressant compound. Ovariectomized female Wistar rats were used in all experiments. In the first experiment, an effective dose of E2 (10 microg/rat, -48 h) was combined with several doses (0.5, 1.0 and 2 mg/kg) of RU 58668 (a pure ER antagonist) 48 h previous to the FST. The second experiment evaluated the action of (1 mg/kg, -48 h or -23, -5 and -1 h) WAY 100635 (5-HT1A receptor antagonist) on the antidepressant-like action of FLX (10 mg/kg, -23, -5 and -1 h). In the third experiment, the effect of RU 58668 (2 mg/kg, -48) or WAY 100635 (1 mg/kg, -48 h) on the antidepressant-like action of the combination of a sub-optimal dose of E2 (2.5 microg/rat, -48 h) plus a non-effective dose of FLX (2.5 mg/kg, -23,-5 and -1 h) was evaluated. The results showed that RU 58668, the antagonist to the ER, canceled the antidepressant-like action of E2 in a dose-dependent manner. The antagonist to the 5-HT1A receptor blocked the antidepressant action of FLX only when administered simultaneously with FLX, i.e. -23, -5 and -1 h before the FST. Finally, the administration of both RU 58668, and WAY100635 canceled the antidepressant-like action of the combination of E2/FLX. These results imply that both 5-HT1A receptors and ERs participate in the facilitating actions of E2 on the antidepressant-like action of FLX in the FST.     

Antidepressant-like effect of Valeriana glechomifolia Meyer (Valerianaceae) in mice

The antidepressant-like effect of a supercritical CO₂ (SCCO₂) Valeriana glechomifolia extract enriched in valepotriates was investigated in a mice tail suspension test (TST) and forced swimming test (FST). The SCCO₂ extract decreased mice immobility in the FST (0.5-20 mg/kg p.o.) and elicited a biphasic dose-response relationship in the TST (1-20 mg/kg p.o.) with no alterations in locomotor activity and motor coordination (assessed in the open-field and rota-rod tests, respectively). The anti-immobility effect of the SCCO₂ extract (5 mg/kg, p.o.) was prevented by mice pre-treatment with yohimbine (1 mg/kg, i.p., an α2 adrenoceptor antagonist), SCH 23390 (15 μg/kg, s.c., D₁ dopamine receptor antagonist) and sulpiride (50 mg/kg, i.p., D₂ dopamine receptor antagonist). However, mice pre-treatments with prazosin (1 mg/kg, i.p., α1 adrenoceptor antagonist) and p-chlorophenilalanine methyl ester (4 × 100 mg/kg/day, i.p., a serotonin synthesis inhibitor) were not able to block the anti-immobility effect of the SCCO₂ extract. Administration (p.o.) of the SCCO₂ extract (0.25 mg/kg) and imipramine (10 mg/kg), desipramine (5 mg/kg) and bupropion (3 mg/kg) at sub-effective doses significantly reduced mice immobility time in the FST. These data provide the first evidence of the antidepressant-like activity of V. glechomifolia valepotriates, which is due to an interaction with dopaminergic and noradrenergic neurotransmission.     

Involvement of L-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of tramadol in the rat forced swimming test

Tramadol is a centrally acting analgesic which is used mainly for the treatment of moderate or severe pain. It is a synthetic opioid in the aminocyclohexanol group that binds weakly to μ-opioid receptors. Since it has been suggested that both opioid and monoaminergic systems play a role in depressive disorders, tramadol has been studied in the forced swimming test (FST). The present study was designed to explore the antidepressant activity of tramadol in rat FST and its possible mechanisms of action. The involvement of l-arginine–nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of tramadol was investigated. Treatment with tramadol, given (30 min earlier) by oral route (p.o.) at the doses of 10, 20 and 40 mg/kg, decreased immobility time in the FST. Pretreatment of rats with l-arginine (250 mg/kg, intraperitoneal, i.p., a nitric oxide precursor) or sildenafil (5 mg/kg, i.p., a phosphodiesterase 5 inhibitor, PDE5) significantly reversed the reduction in immobility time elicited by tramadol (20 mg/kg, p.o.) in the FST. Treatment of animals with a sub-effective dose of tramadol (5 mg/kg, p.o.) produced a synergistic antidepressant-like effect with N^G-nitro-l-arginine (L-NNA, 3 mg/kg, i.p., an inhibitor of nitric oxide synthase) or with 7-nitroindazole (7-NI, 9 mg/kg i.p., a specific neuronal nitric oxide synthase inhibitor) in the FST. Pretreatment of animals with methylene blue (3.75 mg/kg i.p., an inhibitor of NO synthase and soluble guanylate cyclase — sGC) or (1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one) (ODQ, 2 mg/kg, i.p., a specific inhibitor of sGC) significantly caused a synergistic effect with a sub-effective dose of tramadol (5 mg/kg, p.o.) in the FST. In the present study, different doses of tramadol and the combination with the l-arginine–NO–cGMP pathway modulators had no effect on the locomotor activity of rats in the open-field test. Thus, our findings suggest that the acute administration of tramadol produces antidepressant-like effect in the rat FST by a mechanism that involves the inhibition of l-arginine–NO–cGMP pathway.     

Uliginosin B, a phloroglucinol derivative from Hypericum polyanthemum: a promising new molecular pattern for the development of antidepressant drugs

In this study we have demonstrated that cyclohexane extract of Hypericum polyanthemum (POL) and its main phloroglucinol derivative uliginosin B (ULI) present antidepressant-like activity in rodent forced swimming test (FST). The involvement of monoaminergic neurotransmission on the antidepressant-like activity of ULI was evaluated in vivo and in vitro. POL 90 mg/kg (p.o.) and ULI 10 mg/kg (p.o.) reduced the immobility time in the mice FST without altering locomotion activity in the open-field test. The combination of sub-effective doses of POL (45 mg/kg, p.o.) and ULI (5 mg/kg, p.o.) with sub-effective doses of imipramine (10 mg/kg, p.o.), bupropion (3 mg/kg, p.o.) and fluoxetine (15 mg/kg, p.o.) induced a significant reduction on immobility time in FST. The pretreatment with SCH 23390 (15 μg/kg, s.c., dopamine D1 receptor antagonist), sulpiride (50 mg/kg, i.p., dopamine D2 receptor antagonist), prazosin (1 mg/kg, i.p., α1-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., α2-adrenoceptor antagonist) and pCPA (100 mg/kg/day, i.p., p-chlorophenilalanine methyl ester, inhibitor of serotonin synthesis, for four consecutive days) before ULI administration (10 mg/kg, p.o.) significantly prevented the anti-immobility effect in FST. ULI was able to inhibit synaptosomal uptake of dopamine (IC₅₀ = 90 ± 38 nM), serotonin (IC₅₀ = 252 ± 13 nM) and noradrenaline (280 ± 48 nM), but it did not bind to any of the monoamine transporters. These data firstly demonstrated the antidepressant-like effect of POL and ULI, which depends on the activation of the monoaminergic neurotransmission in a different manner from the most antidepressants.     

Antidepressant-like action of the ethanolic extract from Tabebuia avellanedae in mice: Evidence for the involvement of the monoaminergic system

The antidepressant-like effect of the ethanolic extract obtained from barks of Tabebuia avellanedae, a plant widely employed in folk medicine, was investigated in two predictive models of depression: forced swimming test (FST) and tail suspension test (TST) in mice. Additionally, the mechanisms involved in this antidepressant-like action and the effects of the association of the extract with the antidepressants fluoxetine, desipramine and bupropion in the TST were investigated. The extract from T. avellanedae produced an antidepressant-like effect, in the FST (100 mg/kg, p.o.) and in the TST (10–300 mg/kg, p.o.), without accompanying changes in ambulation when assessed in the open-field test. The anti-immobility effect of the extract (30 mg/kg, p.o.) in the TST was prevented by pre-treatment of mice with ketanserin (5 mg/kg, i.p., a preferential 5-HT_2A receptor antagonist), prazosin (1 mg/kg, i.p., an α₁-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an α₂-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a β-adrenoceptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D₂ receptor antagonist) and SCH23390 (0.05 mg/kg, s.c., a dopamine D₁ receptor antagonist). The combined administration of a subeffective dose of WAY100635 (0.1 mg/kg, s.c., a selective 5-HT_1A receptor antagonist) and a subeffective dose of the extract (1 mg/kg, p.o.) produced a significant reduction in the immobility time in the TST. In addition, the combination of fluoxetine (1 mg/kg, p.o.), desipramine (0.1 mg/kg, p.o.), or bupropion (1 mg/kg, p.o.) with a subeffective dose of the extract (1 mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST, without causing hyperlocomotion in the open-field test. It may be concluded that the extract from T. avellanedae produces an antidepressant-like effect in the FST and in the TST that is dependent on the monoaminergic system. Taken together, our results suggest that T. avellanedae deserves further investigation as a putative alternative therapeutic tool that could help the conventional pharmacotherapy of depression.     

Reversal by quercetin of corticotrophin releasing factor induced anxiety- and depression-like effect in mice

Quercetin is a bioflavonoid reported to produce variety of behavioral effects like anxiolytic, antidepressant, etc. Recent gathering evidences indicated that quercetin attenuates stress-induced behavioral and biochemical effects. It also decreases CRF expression in the brain. As CRF is commonly implicated in the high-anxiety and depression, we hypothesized that quercetin may involve CRF in its anxiolytic- and antidepressant-like effects. To support such possibility, we investigated the influence of quercetin on CRF or CRF antagonist (antalarmin) induced changes in social interaction time in social interaction test, and immobility time in forced swim test. Results indicated that quercetin (20–40 mg/kg, p.o.) or antalarmin (2–4 µg/mouse, i.c.v.) dose dependently increased social interaction time and decreased immobility time indicating anxiolytic- and antidepressant-like effect. These effects were comparable with the traditional anxiolytic (diazepam, 1-2 mg/kg, i.p.) and antidepressant (fluoxetine, 10–20 mg/kg, i.p.) agents. Administration of CRF (0.1 and 0.3 nmol/mouse, i.c.v.) produced just opposite effects to that of quercetin on these parameters. Further, it was seen that pretreatment with quercetin (20 or 40 mg/kg, p.o.) dose dependently antagonized the effects of CRF (0.1 or 0.3 nmol/mouse, i.c.v.) in social interaction and forced swim test. The sub-effective dose of antalarmin (1 µg/mouse) when administered along with the sub-effective dose of quercetin (10 mg/kg) produced significant anxiolytic-and antidepressant-like effect. These observations suggest reciprocating role of quercetin on the CRF-induced anxiogenic and depressant-like effects.     

Involvement of L-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of venlafaxine in mice

The involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of venlafaxine (dual serotonin and norepinephrine reuptake inhibitor) was investigated in mice. The antidepressant activity was assessed in forced swim test (FST) behavioral paradigm. Total immobility time was registered during the period of 6 min. Venlafaxine produced dose-dependent (4-16 mg/kg, i.p.) reduction in immobility period. The antidepressant-like effect of venlafaxine (8 mg/kg, i.p.) was prevented by pretreatment with l-arginine (750 mg/kg, i.p.) [substrate for nitric oxide synthase (NOS)]. Pretreatment of mice with 7-nitroindazole (7-NI) (25 mg/kg, i.p.) [a specific neuronal nitric oxide synthase (nNOS) inhibitor] produced potentiation of the action of subeffective dose of venlafaxine (2 mg/kg, i.p.). In addition, treatment of mice with methylene blue (10 mg/kg, i.p.) [direct inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] potentiated the effect of venlafaxine (2 mg/kg, i.p.) in the FST. Furthermore, the reduction in the immobility time elicited by venlafaxine (8 mg/kg, i.p.) was also inhibited by pretreatment with sildenafil (5 mg/kg, i.p.) [phosphodiesterase 5 inhibitor]. The various modulators used in the study did not produce any changes in locomotor activity per se. The results demonstrated that the antidepressant-like effect of venlafaxine in the FST involved an interaction with the L-arginine-NO-cGMP pathway.     

Effects of nicotine on depressive-like behavior and hippocampal volume of female WKY rats

The observed high incidence of smoking amongst depressed individuals has led to the hypothesis of ‘self medication” with nicotine in some of these patients. The inbred Wistar–Kyoto (WKY) rats exhibit depressive-like characteristics as evidenced by exaggerated immobility in the forced swim test (FST). One aim of this study was to investigate whether nicotine may have an antidepressant-like effect in these animals. Moreover, because of human postmortem studies indicating a reduction of the hippocampus volume in depressed patients, it was of interest to determine whether such an anatomical anomaly may also be manifested in WKY rats and whether it would be affected by chronic nicotine treatment. Adult female WKY and their control Wistar rats were administered nicotine consecutively (0.2 mg/kg, i.p., once or twice daily for 14 days) and their activity in an open field, as well as their immobility in FST were assessed either 15 min or 18 h after the last injection. Another set of animals was treated twice daily with 0.2 mg/kg nicotine for 14 days and sacrificed on day 15 for stereological evaluation of the hippocampal volume. When tested 15 min after the last injection, once or twice daily nicotine exacerbated the immobility in the FST in WKY rats only. When tested 18 h after the last injection, only twice daily nicotine treatment resulted in less immobility in the FST in WKY rats. Open field locomotor activity was not affected by any nicotine regimen. WKY rats had significantly less hippocampal volume (approximately 20%) than Wistar rats which was not altered by nicotine. These findings further validate the use of WKY rats as an animal model of human depression and signify the importance of inherent genetic differences in final behavioral outcome of nicotine.     

Topiramate and phenytoin anti-immobility effect in the mice forced swimming test is reversed by veratrine: Implication for bipolar depression treatment

Topiramate and phenytoin possess mood stabilizing properties. The mechanism of action of anticonvulsants used in the treatment of bipolar depression is complex and still not completely elucidated. Na⁺ channels are present at distinct sites in neurons, where they sub serve different functions and play distinct roles. The fact that most of the anticonvulsants used in the treatment of bipolar disorders are blockers of voltage-gated Na channels has determined our interest in evaluating the role of ion channels in bipolar disorders.

Objectives

The scope of this study was to determinate if sodium channels are important for topiramate and phenytoin to exert their antidepressant-like functioning.

Methods

The role of Na⁺ channels in the mechanism of action of the anticonvulsants was investigated by using veratrine a selective activator of Na channels in a mice model of depression, the forced swimming test. Veratrine 0.125 mg/kg and topiramate or phenytoin (16 and 32 mg/kg) were given IP 45 and 30 min, respectively, before the test.

Results

The administration of topiramate and phenytoin induce a decrease in the immobility time on the FST which can be considered as an antidepressant-like activity. The antidepressant-like effect of the anticonvulsants was completely reversed by veratrine suggesting that the antidepressant-like effect of topiramate and phenytoin on the FST might be due to their Na⁺ channels blocking properties.     

Antidepressant-like effect of the novel thiadiazolidinone NP031115 in mice

Glycogen synthase kinase-3beta (GSK-3beta) is an enzyme that phosphorylates glycogen synthase, thereby inhibiting glycogen synthesis. Besides this role, it is now believed that this enzyme plays an important role in the pathophysiology of many brain diseases including depression. Some inhibitors of this enzyme have shown antidepressant effects in animal models. This study investigated the effects of a novel thiadiazolidinone NP031115, a putative GSK-3beta inhibitor, and the well-established GSK-3beta inhibitor AR-A014418 in the mouse forced swimming test (FST), a model widely used to evaluate antidepressant activity. We found that NP031115 had an IC50 of 1.23 and 6.5 microM for GSK-3beta and GSK-3alpha, respectively. NP031115 (0.5 and 5 mg/kg, i.p.), in a way similar to imipramine (15 mg/kg, i.p), fluoxetine (32 mg/kg, i.p), AR-A014418 (9 mg/kg, i.p.), and rosiglitazone (5 microg/site, i.c.v.), significantly reduced immobility time in the FST. NP031115 at the higher dose and AR-A014418 (9 mg/kg, i.p.) reduced locomotion in the open-field test. Rosiglitazone (30 microM), AR-A014418 (1 microM), PG(J2) (10 microM), and NP031115 (1, 10 and 25 microM) activate PPARgamma in CHO transfected cells. GW-9662 (10 microg/site, i.c.v, a PPARgamma antagonist) administered 15 min before NP03115 (5 mg/kg, i.p.) or co-administered with rosiglitazone (5 microg/site, i.c.v.) prevented the antidepressant-like effect of these drugs in the FST. The results of this study show that NP031115 can exhibit an antidepressant effect, likely by inhibiting GSK-3beta and enhancing PPARgamma activity.     

Is switching antidepressants following early nonresponse more beneficial in acute-phase treatment of depression?: a randomized open-label trial

Rationale

Treatment guidelines for major depressive disorder (MDD) recommend a continuous use of antidepressants for several weeks, while recent meta-analyses indicate that antidepressant efficacy starts to appear within 2 weeks and early treatment nonresponse is a predictor of subsequent nonresponse.

Objectives

We prospectively compared 8-week outcomes between switching antidepressants and maintaining the same antidepressant in early nonresponders, to generate a hypothesis on possible benefits of early switching strategy.

Method

Patients with MDD without any treatment history for the current episode were included. When subjects failed to show an early response (i.e., ≥ 20% improvement in the Montgomery-Åsberg Depression Rating Scale (MADRS)) to the initial treatment with sertraline 50 mg at week 2, they were randomly divided into two groups; in the Continuing group, sertraline was titrated at 50-100 mg, whereas sertraline was switched to paroxetine 20-40 mg in the Switching group. A primary outcome measure was a response rate (i.e., ≥ 50% improvement in the MADRS) at week 8.

Results

Among 132 subjects, 41 subjects showed early nonresponse. The Switching group (n = 20) showed a higher rate of responders than the Continuing group (n = 21) (75% vs. 19%: p = 0.002). Further, the Switching group was also superior in the rate of remitters (total score of ≤ 10 in the MADRS) (60% vs. 14%: p = 0.004) and continuous changes in the MADRS (19.0 vs. 7.5: p < 0.001).

Conclusions

Our preliminary findings suggest that patients with MDD who fail to show early response to an initial antidepressant may derive benefits from the early switching antidepressants in the acute-phase treatment of depression.     

Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression

A growing body of evidence has suggested that the dysfunction of glutamatergic systems plays a pivotal role in major depressive disorder (MDD). In clinical studies, an N-methyl-d-aspartate receptor antagonist, ketamine, was shown to exert both rapid and sustained antidepressant effects in patients with treatment-resistant MDD. The objective of the present study was to confirm the rapid onset of action of ketamine and to investigate the mechanisms underlying both the rapid and sustained antidepressant-like effects of ketamine in rodent models of depression. The intraperitoneal administration of ketamine (10 mg/kg) 30 min prior to testing significantly reduced the number of escape failures in the learned helplessness (LH) paradigm in rats in which currently prescribed antidepressants exerted an effect only after repeated administrations. Ketamine also significantly reduced the immobility time in the tail suspension test (TST), and this effect lasted for 72 h, indicating that ketamine may possess a sustained antidepressant-like effect. The rapid antidepressant-like effects of ketamine in both the LH paradigm and the TST were significantly blocked by subcutaneous treatment with 2,3-dihydroxy-6-nitro-7-sulfoamoylbenzo(f)quinoxaline (NBQX), an α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist. In addition, the sustained antidepressant-like effect of ketamine in the TST was partially abolished by treatment with NBQX. In conclusion, we confirmed the faster onset of the action of ketamine, compared with clinically prescribed antidepressants. Moreover, the present results suggested that direct AMPA receptor activation may play an important role in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression, although other mechanisms might be involved in the sustained action.     

Outcome in delusional depression comparing trimipramine monotherapy with a combination of amitriptyline and haloperidol - A double-blind multicenter trial

Background

Patients with delusional depression are difficult to treat. The atypical antidepressant trimipramine was effective in a previous 4-week open label pilot study in patients with this disorder. The major neurobiological effect of trimipramine is the inhibition of the hypothalamic-pituitary-adrenocortical (HPA) system. In delusional depression HPA overactivity is more distinct than in other subtypes of depression. HPA suppression is thought to contribute to the action of trimipramine.

Methods

In a double-blind, randomized, placebo controlled multicenter trial we compared the effects of trimipramine monotherapy versus a combination of amitriptyline and haloperidol. Dosage was increased stepwise from 100 mg up to 400 mg trimipramine and from 100 mg up to 200 mg amitriptyline combined with 2 mg up to 7.5 mg haloperidol. The average dose of trimipramine was higher than that of amitriptyline throughout the trial. During sixth week mean dosage (±standard deviation) were 356.1 ± 61.2 mg trimipramine, 184.0 ± 23.6 mg amitriptyline and 6.3 ± 1.8 mg haloperidol. During six weeks psychometric assessments were performed weekly. For HPA monitoring a dexamethasone/corticotropin-releasing hormone (Dex/CRH) test was performed before active medication and at the end of treatment. Additionally tolerability was monitored by ECG, EEG assessment of extrapyramidal symptoms and akathisia, clinical laboratory routine and recording of blood pressure and heart rate. Adverse events were documented.

Results

94 patients were enclosed into the study. The per protocol sample consisted of 33 patients of the trimipramine group and of 24 patients of the amitriptyline/haloperidol group. The decrease of the Hamilton depression (HAMD) score (24 items) showed non-inferiority of trimipramine compared to amitriptyline/haloperidol. Twenty-eight patients (84.84%) in the trimipramine arm and 17 patients (70.83%) in the amitriptyline/haloperidol arm were responders (HAMD ? 50%). Remission (HAMD < 8) was found in 18 (54.55%) patients after trimipramine and in 11 (45.83%) patients after amitriptyline/haloperidol. No significant differences were found concerning response and remission. The cortisol and ACTH response in the Dex/CRH test decreased between days 1 and 42 in both groups. Serious side effects were not reported.

Conclusion

In all, trimipramine monotherapy appears to be an effective treatment in delusional depression.     

Possible involvement of PPAR-gamma receptor and nitric oxide pathway in the anticonvulsant effect of acute pioglitazone on pentylenetetrazole-induced seizures in mice

Besides the receptor-mediated effects of pioglitazone, the involvement of nitric oxide (NO) has been previously demonstrated in some pioglitazone-induced central and peripheral effects. In the present study, the effects of acutely administered pioglitazone on pentylenetetrazole (PTZ)-induced seizures and involvement of NO were evaluated in mice. To determine the threshold for clonic seizures, PTZ was administered intravenously. A single dose of pioglitazone (10, 20, 40 and 80 mg/kg, p.o.) was administered either 2 or 4h prior to induction of seizures. For determination of possible role of peroxisome proliferator activated receptor gamma (PPAR-γ) and nitric oxide pathway in this effect, the effects of a PPAR-γ antagonist, GW9662 (2 mg/kg); a non-specific nitric oxide synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 0.3, 1, 3, and 10 mg/kg); a specific iNOS inhibitor, aminoguanidine (100mg/kg, i.p.) or a nitric oxide precursor, L-arginine (30, 60, 100 and 200mg/kg, i.p.); each administered 15 min prior to pioglitazone, were investigated on the anticonvulsant effect of this drug. Administration of pioglitazone (40 and 80 mg/kg) increased the threshold of PTZ-induced seizure in a dose-dependent, and time-dependent manner. GW9662 reversed the anticonvulsant effect of pioglitazone (40 mg/kg). Acute administration of L-NAME (1, 3 and 10mg/kg) inhibited the anticonvulsant effect of pioglitazone (40 mg/kg), the same result was detected with aminoguanidine (100mg/kg); whereas L-arginine, in the noneffective dose (100mg/kg), potentiated the seizure threshold when co-administered with a subeffective dose of pioglitazone (20mg/kg). CONCLUSION: The present study demonstrates the anticonvulsant effect of acute pioglitazone on PTZ-induced seizures in mice. This effect was reversed by PPAR-γ antagonist, and both a specific- and a non-specific nitric oxide synthase inhibitors, and augmented by nitric oxide precursor, L-arginine. These results support that the anticonvulsant effect of pioglitazone is mediated through PPAR-γ receptor-mediated pathway and also, at least partly, through the nitric oxide pathway.